A Reflux Linked GATA Factor Fulcrum Dictates Lineage Commitment Through GPRC5B During the Esophageal Dysplastic TransitionSummary
Background & Aims: GATA family transcription factors are somatically variable (SV) in esophageal adenocarcinomas (EAC) and inducible by simulated reflux. Our study examines the mechanisms whereby GATA family members (GATA4, GATA6, and the atypical TRPS-1) influence oncogenesis during the Bar...
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Elsevier
2025-01-01
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| Series: | Cellular and Molecular Gastroenterology and Hepatology |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352345X25000931 |
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| author | Omar Abuhussein Sara Hosseini-Farahabadi Corina Stewart Stephane Flibotte Alireza Heravi-Moussavi David Farnell David Schaeffer Fergal Donnellan Frank McKeon Wa Xian Dermot Kelleher Shane Patrick Duggan |
| author_facet | Omar Abuhussein Sara Hosseini-Farahabadi Corina Stewart Stephane Flibotte Alireza Heravi-Moussavi David Farnell David Schaeffer Fergal Donnellan Frank McKeon Wa Xian Dermot Kelleher Shane Patrick Duggan |
| author_sort | Omar Abuhussein |
| collection | DOAJ |
| description | Background & Aims: GATA family transcription factors are somatically variable (SV) in esophageal adenocarcinomas (EAC) and inducible by simulated reflux. Our study examines the mechanisms whereby GATA family members (GATA4, GATA6, and the atypical TRPS-1) influence oncogenesis during the Barrett’s esophagus (BE) metaplasia-dysplasia transition preceding EAC. Methods: RNAseq analyses of esophageal cell lines and lesion-derived adult stem cells (ASCs) in conjunction shRNA- or CRISPR-facilitated gene silencing, together with reanalysis of The Cancer Genome Atlas data, spatial transcriptomics, and organ-on-a-chip studies were used. Results: Although a gastroesophageal reflux disease history positively correlated with GATA4/6 somatically variable and a columnar-associated gene signature (ANPEP/GATA4) in The Cancer Genome Atlas EAC cases, it negatively associated with a squamous lineage-linked signature (TP63/SOX15) containing TRPS1. In experimental data, opposing effects on regulators of squamous and columnar lineage identity were uncovered between TRPS1 and classical GATA factors (GATA4/6). Interrogation of this GATA “fulcrum” defined further genes (CGN, IL6R, and GPRC5B) targeted for TRPS1-mediated suppression or GATA4/6 activation. A novel spatial transcriptomic signature of BE-associated high-grade dysplasia (HGD) captured GATA fulcrum action, through GPRC5B expression. Functionally, GPRC5B was found to be low-pH-responsive, to increase proliferative and colony formation rates, and when overexpressed facilitate a hyperproliferative HGD-like transformation of BE-ASCs. Using an organ-on-a-chip platform, cellular overgrowth, reduced luminal villus structures, lower goblet cell numbers, and loss of intestine-associated marker gene expression (TFF3/MUC2) were observed following GPRC5B overexpression in BE-ASCs, mirroring HGD. Conclusions: This study identifies critical GATA factor-mediated processes underlying cellular phenotype in the BE-HGD-EAC transition and identifies GATA-inducible GPRC5B as a functional marker and possible driver of progression through HGD to EAC. |
| format | Article |
| id | doaj-art-bcbdacc888eb4eaabbf8f05a4f6b0053 |
| institution | Kabale University |
| issn | 2352-345X |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Elsevier |
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| series | Cellular and Molecular Gastroenterology and Hepatology |
| spelling | doaj-art-bcbdacc888eb4eaabbf8f05a4f6b00532025-08-20T03:32:57ZengElsevierCellular and Molecular Gastroenterology and Hepatology2352-345X2025-01-01191010155210.1016/j.jcmgh.2025.101552A Reflux Linked GATA Factor Fulcrum Dictates Lineage Commitment Through GPRC5B During the Esophageal Dysplastic TransitionSummaryOmar Abuhussein0Sara Hosseini-Farahabadi1Corina Stewart2Stephane Flibotte3Alireza Heravi-Moussavi4David Farnell5David Schaeffer6Fergal Donnellan7Frank McKeon8Wa Xian9Dermot Kelleher10Shane Patrick Duggan11Division of Gastroenterology, Department of Medicine, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada; Life Sciences Institute, University of British Columbia, Vancouver, British Columbia, CanadaDivision of Gastroenterology, Department of Medicine, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada; Life Sciences Institute, University of British Columbia, Vancouver, British Columbia, CanadaDivision of Gastroenterology, Department of Medicine, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada; Life Sciences Institute, University of British Columbia, Vancouver, British Columbia, CanadaLife Sciences Institute, Bioinformatics Facility, University of British Columbia, Vancouver, British Columbia, CanadaBritish Columbia’s Genome Science Centre, Vancouver, British Columbia, CanadaVancouver General Hospital, Vancouver, British Columbia, Canada; Vancouver Coastal Health Research Institute, Vancouver, British Columbia, CanadaVancouver General Hospital, Vancouver, British Columbia, Canada; Vancouver Coastal Health Research Institute, Vancouver, British Columbia, CanadaVancouver General Hospital, Vancouver, British Columbia, Canada; Vancouver Coastal Health Research Institute, Vancouver, British Columbia, CanadaDepartment of Biochemistry and Molecular Biology and the Somatic Stem Cell Center, University of Houston, Houston, TexasDepartment of Biochemistry and Molecular Biology and the Somatic Stem Cell Center, University of Houston, Houston, TexasDivision of Gastroenterology, Department of Medicine, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada; Life Sciences Institute, University of British Columbia, Vancouver, British Columbia, Canada; Dermot Kelleher, MD, Life Science Institute, 2350 Health Science Mall, University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z3.Division of Gastroenterology, Department of Medicine, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada; Life Sciences Institute, University of British Columbia, Vancouver, British Columbia, Canada; Correspondence Address correspondence to: Shane Duggan, PhD, Life Science Institute, 2350 Health Science Mall, University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z3.Background & Aims: GATA family transcription factors are somatically variable (SV) in esophageal adenocarcinomas (EAC) and inducible by simulated reflux. Our study examines the mechanisms whereby GATA family members (GATA4, GATA6, and the atypical TRPS-1) influence oncogenesis during the Barrett’s esophagus (BE) metaplasia-dysplasia transition preceding EAC. Methods: RNAseq analyses of esophageal cell lines and lesion-derived adult stem cells (ASCs) in conjunction shRNA- or CRISPR-facilitated gene silencing, together with reanalysis of The Cancer Genome Atlas data, spatial transcriptomics, and organ-on-a-chip studies were used. Results: Although a gastroesophageal reflux disease history positively correlated with GATA4/6 somatically variable and a columnar-associated gene signature (ANPEP/GATA4) in The Cancer Genome Atlas EAC cases, it negatively associated with a squamous lineage-linked signature (TP63/SOX15) containing TRPS1. In experimental data, opposing effects on regulators of squamous and columnar lineage identity were uncovered between TRPS1 and classical GATA factors (GATA4/6). Interrogation of this GATA “fulcrum” defined further genes (CGN, IL6R, and GPRC5B) targeted for TRPS1-mediated suppression or GATA4/6 activation. A novel spatial transcriptomic signature of BE-associated high-grade dysplasia (HGD) captured GATA fulcrum action, through GPRC5B expression. Functionally, GPRC5B was found to be low-pH-responsive, to increase proliferative and colony formation rates, and when overexpressed facilitate a hyperproliferative HGD-like transformation of BE-ASCs. Using an organ-on-a-chip platform, cellular overgrowth, reduced luminal villus structures, lower goblet cell numbers, and loss of intestine-associated marker gene expression (TFF3/MUC2) were observed following GPRC5B overexpression in BE-ASCs, mirroring HGD. Conclusions: This study identifies critical GATA factor-mediated processes underlying cellular phenotype in the BE-HGD-EAC transition and identifies GATA-inducible GPRC5B as a functional marker and possible driver of progression through HGD to EAC.http://www.sciencedirect.com/science/article/pii/S2352345X25000931High-Grade DysplasiaEsophageal AdenocarcinomaGastroesophageal Reflux DiseaseOrgan-On-A-ChipBarrett’s Esophagus |
| spellingShingle | Omar Abuhussein Sara Hosseini-Farahabadi Corina Stewart Stephane Flibotte Alireza Heravi-Moussavi David Farnell David Schaeffer Fergal Donnellan Frank McKeon Wa Xian Dermot Kelleher Shane Patrick Duggan A Reflux Linked GATA Factor Fulcrum Dictates Lineage Commitment Through GPRC5B During the Esophageal Dysplastic TransitionSummary Cellular and Molecular Gastroenterology and Hepatology High-Grade Dysplasia Esophageal Adenocarcinoma Gastroesophageal Reflux Disease Organ-On-A-Chip Barrett’s Esophagus |
| title | A Reflux Linked GATA Factor Fulcrum Dictates Lineage Commitment Through GPRC5B During the Esophageal Dysplastic TransitionSummary |
| title_full | A Reflux Linked GATA Factor Fulcrum Dictates Lineage Commitment Through GPRC5B During the Esophageal Dysplastic TransitionSummary |
| title_fullStr | A Reflux Linked GATA Factor Fulcrum Dictates Lineage Commitment Through GPRC5B During the Esophageal Dysplastic TransitionSummary |
| title_full_unstemmed | A Reflux Linked GATA Factor Fulcrum Dictates Lineage Commitment Through GPRC5B During the Esophageal Dysplastic TransitionSummary |
| title_short | A Reflux Linked GATA Factor Fulcrum Dictates Lineage Commitment Through GPRC5B During the Esophageal Dysplastic TransitionSummary |
| title_sort | reflux linked gata factor fulcrum dictates lineage commitment through gprc5b during the esophageal dysplastic transitionsummary |
| topic | High-Grade Dysplasia Esophageal Adenocarcinoma Gastroesophageal Reflux Disease Organ-On-A-Chip Barrett’s Esophagus |
| url | http://www.sciencedirect.com/science/article/pii/S2352345X25000931 |
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